Obesity is a major risk factor for type II diabetes and cardiovascular disease. Increased understanding of body weight regulation may lead to effective strategies to combat obesity. Hypothalamic neurons, including pro-opiomelanocortin (POMC) neurons and steroidogenic factor-1 (SF1) neurons, integrate multiple metabolic cues to provide a coordinated control of energy homeostasis. In our pilot studies, we found that a nuclear receptor co-activator, namely steroid receptor co-activator-1 (SRC1), is expressed in majority of POMC and SF1 neurons. We observed that hypothalamic SRC1 interacts with pSTAT3 and SF1. In particular, the hypothalamic SRC1-pSTAT3 interaction can be enhanced by leptin, but is disrupted in mice with diet-induced obesity (DIO). Importantly, we observed the similar SRC1-pSTAT3 dissociation in the hypothalami from obese humans. These raise the hypotheses that (1) SRC1 in POMC and/or SF1 neurons mediate leptin actions through its interactions with pSTAT3 or SF1; (2) the dysfunction of hypothalamic SRC1 contributes to the development of DIO; (3) interventions enhancing hypothalamic SRC1 functions interaction can be used to prevent or treat obesity. Consistent with this, we found that SRC1lox/lox/POMC-Cre mice, which lack SRC1 in both mature and developing POMC neurons, are less sensitive to leptin-induced anorexia and more susceptible to DIO. Importantly, we identified a small chemical that enhances the hypothalamic SRC1-pSTAT3 interaction and partially prevents DIO. Objectives of the current application are to generate mice lacking or overexpressing SRC1 only in mature POMC neurons (Aim 1) or SF1 neurons (Aim 2), and systemically examine the effects of such deletion/overexpression on energy homeostasis and leptin sensitivity. In addition, a series of in vivo and in vitro experiments are designed to explore the molecular mechanisms by which hypothalamic SRC1 interacts with pSTAT3 and SF1, and regulates their transcriptional activities. Finally, we will continue to test the anti-obesity efficacy of the small chemical in a number of rodent obese models and to explore molecular mechanisms and action targets of the chemical. Thus, these experiments may reveal novel mechanisms underlying the development of obesity, identify hypothalamic SRC1 as a rational target for the treatment of obesity, and lead to discovery of an obesity drug candidate suitable for clinical trials.